Crystalline forms of valacyclovir hydrochloride

ABSTRACT

Provided are novel polymorphs and pseudopolymorphs of valacyclovir hydrochloride and pharmaceutical compositions containing these. Also provided are methods for making the novel polymorphs and pseudopolymorphs, which include valacyclovir hydrochloride monohydrate and valacyclovir hydrochloride dihydrate.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the following U.S.Provisional Applications No. 60/317,850, filed Sep. 7, 2001; No.60/342,273, filed Dec. 21, 2001; No. 60/386,505, filed Jun. 5, 2002; andNo. 60/403,838, filed Aug. 14, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates to novel crystalline forms(polymorphs and pseudopolymorphs) of the antiviral compound valacyclovirhydrochloride, and methods for obtaining them.

BACKGROUND

[0003] Valacyclovir is an L-valyl ester prodrug of acyclovir. Acycloviris an acyclic analog of a natural nucleoside which has been found tohave high anti-viral activity. Acyclovir is widely used in the treatmentand prophylaxis of viral infections in humans, particularly infectionscaused by the herpes group of viruses. See Goodman and Gilman's, ThePharmacological Basis of Therapeutics 1193-1198 (9th ed. 1996).

[0004] Acyclovir is an acyclic guanine nucleoside analog that lacks a3′-hydroxyl on the side chain. Acyclovir has the chemical name6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]. (CASRegistry No. 59277-89-3.) Acyclovir as the sodium salt is currentlymarketed as ZOVIRAX®. The chemical structure of acyclovir is shown asFormula I.

[0005] Valacyclovir has the chemical name 1-valine,2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester. (CASRegistry No. 124832-26-4.) Valacyclovir is currently marketed asVALTREX®. The chemical structure of valacyclovir is shown as Formula II.

[0006] For oral administration, it is advantageous to administervalacyclovir rather than acyclovir because acyclovir is poorly absorbedfrom the gastrointestinal tract after oral administration in bothanimals and humans. In contrast, valacyclovir is rapidly absorbed fromthe gastrointestinal tract after oral administration. Moreover,valacyclovir is converted rapidly and virtually completely to acyclovirafter oral administration in healthy adults. The conversion ofvalacyclovir is thought to result from first-pass intestinal and hepaticmetabolism through enzymatic hydrolysis.

[0007] Acyclovir kills viruses by inhibiting viral DNA synthesis.Because acyclovir is a guanosine analog which lacks the 3′-hydroxyl onthe side chain, it causes DNA chain termination during viral DNAreplication. In virus infected cells, acyclovir is converted to themonophosphate derivative (acyclovir-MP) by a viral enzyme, thymidininekinase. Acyclovir-MP is then phosphorylated to the diphosphate andtriphosphate analogs by cellular enzyme. Incorporation of activatedacyclovir into the primer strand during viral DNA replication, leads tochain termination, since without the 3′ hydroxyl the DNA chain can notbe extended. Since uninfected cells lack the viral enzyme thymidinekinase, acyclovir is selectively activated only in cells infected withviruses that code for the appropriate kinases.

[0008] U.S. Pat. No. 4,199,574 discloses the treatment of viralinfections with acyclovir.

[0009] U.S. Pat. No. 4,957,924 (the '924 patent”) discloses amino acidesters of the purine nucleoside acyclovir, pharmaceutically acceptablesalts thereof and their use in the treatment of herpes virus infections.Also disclosed are pharmaceutical formulations and processes for thepreparation of such compounds. Valacyclovir and its salts, including thehydrochloride salt, are among the disclosed compounds.

[0010] The '924 patent further discloses a method for the preparation ofvalacyclovir by condensation of CBZ-Valine and acyclovir in Dimethylformamide (DMF) with catalytic amount of 4-dimethylaminopyridine (DMAP) andDicyclohexylcarbodiimide (DCC) as a coupling reagent.

[0011] U.S. Pat. No. 6,107,302, incorporated herein by reference,discloses an anhydrous crystalline form of valacyclovir hydrochlorideand a process of preparation.

[0012] The discovery of a new crystalline form of a pharmaceuticallyuseful compound provides an opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic. It is clearlyadvantageous when this repertoire is enlarged by the discovery of newcrystalline forms of a useful compound. For a general review ofpolymorphs and the pharmaceutical applications of polymorphs see G. M.Wall, Pharm. Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J.Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64,1269 (1975), all of which are incorporated herein by reference.

[0013] The solid state physical properties of crystalline forms of apharmaceutically useful hydrochloride can be influenced by controllingthe conditions under which the hydrochloride salt is obtained in solidform. Solid state physical properties include, for example, theflowability of the milled solid. Flowability affects the ease with whichthe material is handled during processing into a pharmaceutical product.When particles of the powdered compound do not flow past each othereasily, a formulation specialist must take that fact into account indeveloping a tablet or capsule formulation, which may necessitate theuse of glidants such as colloidal silicon dioxide, talc, starch ortribasic calcium phosphate.

[0014] Another important solid state property of a pharmaceuticalcompound is its rate of dissolution in aqueous fluid. The rate ofdissolution of an active ingredient in a patient's stomach fluid canhave therapeutic consequences since it imposes an upper limit on therate at which an orally-administered active ingredient can reach thepatient's bloodstream. The rate of dissolution is also a considerationin formulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

[0015] These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular crystalline form of a substance. The crystallineform may give rise to thermal behavior different from that of theamorphous material or another crystalline form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC) and can be used to distinguish some crystalline formsfrom others. A particular crystalline form may also give rise todistinct spectroscopic properties that may be detectable by powder X-raycrystallography, solid state ¹³C NMR spectrometry and infraredspectrometry.

BRIEF DESCRIPTION OF THE FIGURES

[0016]FIG. 1 shows a representative X-ray diffraction pattern ofvalacyclovir hydrochloride in form I.

[0017]FIG. 2 shows a representative DTG thermogram of valacyclovirhydrochloride in form I.

[0018]FIG. 3 shows a representative X-ray diffraction pattern ofvalacyclovir hydrochloride in form II.

[0019]FIG. 4 shows a representative DTG thermogram of valacyclovirhydrochloride in form II.

[0020]FIG. 5 shows a representative DTG thermogram of valacyclovirhydrochloride in form IV.

[0021]FIG. 6 shows a representative X-ray diffraction pattern obtainedwhen valacyclovir hydrochloride was incubated in controlled humiditycell having a relative humidity of 100% for 1 week to yield valacyclovirhydrochloride in form IV.

[0022]FIG. 7 shows a representative x-ray diffraction diagram forvalacyclovir hydrochloride in form V.

[0023]FIG. 8 shows representative differential thermal analysis andthermogravimetric thermograms for valacyclovir hydrochloride in form V.

[0024]FIG. 9 shows a representative X-ray diffraction pattern forvalacyclovir hydrochloride in form VI.

[0025]FIG. 10 shows a representative X-ray diffraction pattern forvalacyclovir hydrochloride in form VII.

SUMMARY OF THE INVENTION

[0026] In one aspect, the present invention relates to valacyclovirhydrochloride in crystalline forms I, II, IV, V, VI, and VII as well asadmixtures of two or more of these forms.

[0027] In another aspect, the present invention relates to methods ofmaking forms I, II, III, IV, V, VI and VII and mixtures thereof. Thepresent invention also relates to pharmaceutical compositions containingvalacyclovir hydrochloride in crystalline forms I, II, IV, V, VI, andVII as well as mixtures of two or more of these.

[0028] In one aspect, the present invention relates to valacyclovirhydrochloride in form I, characterized by x-ray diffraction peaks(reflections) at about 3.7, 8.6, 10.6, 10.9, 16.5, 24.0, and 27.2±0.2degrees two-theta.

[0029] In one aspect, the present invention relates to valacyclovirhydrochloride in form I, characterized by x-ray diffraction peaks(reflections) at about 3.7, 8.6, 10.6, 10.9, 16.5, 24.0, and 27.2±0.2degrees two-theta, and further characterized by x-ray diffraction peaks(reflections) at 9.5, 13.3, 20.1, 21.4, and 26.7 degrees two theta.

[0030] In another aspect, the present invention also relates tovalacyclovir hydrochloride in form I having the x-ray powder diffractionpattern substantially as shown in FIG. 1.

[0031] In another aspect, the present invention also relates tovalacyclovir hydrochloride in form I further characterized as having aweight loss of between about 6% and about 9% as measured bythermogravimetric analysis over the temperature range between about 25°C. and about 140° C. This water content corresponds to the stochiometricamount of water in the sesquihydrate and is agreement with water contenddetermined by Karl-Fisher.

[0032] The present invention also relates to a pharmaceuticalcomposition including valacyclovir hydrochloride in form I.

[0033] In another aspect, the present invention also relates tovalacyclovir hydrochloride in form II.

[0034] The present invention also relates to valacyclovir hydrochloridein form II, characterized by x-ray diffraction peaks (reflections) atabout 6.6, 11.5, 17.2, 19.0, 21.5, 27.4 and 28.0±0.2 degrees two-theta.

[0035] In another aspect, the present invention also relates tovalacyclovir hydrochloride in form II, characterized by x-raydiffraction peaks (reflections) at about 6.6, 11.5, 17.2, 19.0, 21.5,27.4 and 28.0±0.2 degrees two-theta, and further characterized byadditional x-ray diffraction peaks (reflections) at 9.2, 15.6, and26.3±0.2 degrees two-theta.

[0036] The present invention also relates to valacyclovir hydrochloridein form II, further characterized as having an endothermic peak at about211° C. through differential thermal analysis.

[0037] The present invention also relates to valacyclovir hydrochloridein form II having the X-ray powder diffraction pattern substantially asshown in FIG. 3.

[0038] The present invention also relates to a pharmaceuticalcomposition including valacyclovir hydrochloride form II.

[0039] In another aspect, the present invention relates to valacyclovirhydrochloride form IV.

[0040] In yet another aspect, the present invention relates tovalacyclovir hydrochloride form IV, characterized by x-ray diffractionpeaks at about 3.6, 10.7, 15.1, 26.9, and 28.1±0.2 degrees two-theta.

[0041] In yet another aspect, the present invention relates tovalacyclovir hydrochloride form IV, characterized by x-ray diffractionpeaks at about 3.6, 10.7, 15.1, 26.9, and 28.1±0.2 degrees two-theta,and further characterized by x-ray diffraction peaks (reflections) at7.2, 8.7, 9.5, 13.3, 16.5, 23.5, and 24.0 degrees two-theta.

[0042] In another aspect, the present invention relates to valacyclovirhydrochloride in form IV further characterized by additional x-raydiffraction reflections at about 7.2°, 8.6°, 9.5°, 13.3°, 15.2°, 27.3°,and 28.1°±0.2° two-theta.

[0043] The present invention also relates to valacyclovir hydrochlorideform IV having the X-ray powder diffraction pattern substantially asshown in FIG. 6

[0044] In another aspect, the present invention relates to valacyclovirhydrochloride form IV further characterized as having a weight loss ofbetween about 9% and about 11% as measured by thermogravimetric analysisover the temperature range between about 25° C. and about 170° C. ThisLOD value corresponds to the stoichiometric amount of water determinedby the Karl-Fisher method.

[0045] The present invention also relates to a pharmaceuticalcomposition including valacyclovir hydrochloride form IV.

[0046] In one aspect, the present invention relates to valacyclovirhydrochloride in crystalline form V.

[0047] In another aspect, the present invention also relates tovalacyclovir hydrochloride in form V having the X-ray powder diffractionpattern substantially as shown in FIG. 12.

[0048] In another aspect, the present invention relates to valacyclovirhydrochloride in form V having x-ray reflections (peaks) at about 6.7°,15.7°, 16.2°, and 22.60±10.2° 2θ.

[0049] In another aspect, the present invention relates to valacyclovirhydrochloride in form V having additional x-ray reflections (peaks) atabout 3.4°, 9.5°, 13.5°, 21.9°, 27.2°, and 28.60±0.2° 2θ.

[0050] In another aspect, the present invention relates to valacyclovirhydrochloride in form V further characterized as having a weight loss ofbetween about 5% and about 7% as measured by thermogravimetric analysisover the temperature range between about 25° C. and about 130° C.

[0051] In another aspect, the present invention relates to valacyclovirhydrochloride in form V further characterized by a broad endothermicpeak at about 95° C. and a sharp endothermic peak at about 180° C. asexhibited by differential thermogravimetric analysis.

[0052] The present invention also relates to pharmaceutical compositionsincluding valacyclovir hydrochloride in form V.

[0053] In yet another aspect, the present invention relates tovalacyclovir hydrochloride in crystalline in form VI.

[0054] In another aspect, the present invention relates to valacyclovirhydrochloride in form VI characterized by x-ray diffraction peaks(reflections) at about 6.2°, 9.2°, 12.1°, 20.2° and 25.7°±0.2° 2θ.

[0055] In another aspect, the present invention relates to valacyclovirhydrochloride in form VI characterized by the x-ray powder diffractionpattern substantially as shown in FIG. 14.

[0056] The present invention also relates to pharmaceutical compositionsincluding valacyclovir hydrochloride in form VI.

[0057] In another aspect, the present invention relates to valacyclovirhydrochloride in crystalline form VII.

[0058] In still another aspect, the present invention relates tovalacyclovir hydrochloride in form VII characterized by an X-raydiffraction pattern having peaks (reflections) at about 3.5°, 10.3°,13.6°, 26.2° and 28.1° 2θ.

[0059] In still another aspect, the present invention relates tovalacyclovir hydrochloride in form VII characterized by the x-ray powderdiffraction pattern substantially as shown in FIG. 15.

[0060] The present invention also relates to pharmaceutical compositionsincluding valacyclovir hydrochloride in form VII.

[0061] In another aspect, the present invention also relates to aprocess for preparing valacyclovir hydrochloride form I, including thestep of suspending valacyclovir hydrochloride as a slurry in a slurrysolvent, wherein the slurry solvent is selected from the group that isethyl acetate, acetone, methyl ethyl ketone, dioxane, methylenechloride, t-butyl methyl ether, and tetrahydrofurane.

[0062] In another aspect, the present invention also relates to aprocess for preparing valacyclovir hydrochloride in form I, includingthe steps of suspending valacyclovir hydrochloride as a slurry in aslurry solvent, wherein the slurry solvent is selected from the groupthat is ethyl acetate, acetone, methyl ethyl ketone, dioxane, methylenechloride, t-butyl methyl ether, and tetrahydrofurane; isolatingvalacyclovir hydrochloride in form I from the slurry; and dryingvalacyclovir form I at a temperature between about 20° C. and about 70°C.

[0063] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form II including the step ofslurrying, at ambient temperature, valacyclovir hydrochloride in aslurry solvent selected from isopropyl alcohol, 1-butanol, or ethanol.

[0064] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form II including the step ofslurrying valacyclovir hydrochloride in toluene and, optionally,isolating valacyclovir hydrochloride in form II from the slurry anddrying the valacyclovir hydrochloride form II, preferably at atemperature of about 60° C. Optionally, drying is at a pressure lessthan about 500 mm Hg and a temperature of about 50° C.

[0065] In yet another aspect, the present invention relates to a refluxslurry method of making valacyclovir hydrochloride in form II includingthe steps of slurrying valacyclovir in a slurry solvent selected fromacetonitrille, methyl ethyl ketone, ethyl acetate, acetone, and toluene,heating the slurry to reflux, refluxing the resulting mixture, andisolating valacyclovir hydrochloride in form II from the mixture.

[0066] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form II including the steps ofslurrying valacyclovir hydrochloride in toluene; heating the slurry toreflux; adding methanol to the slurry; refluxing the resulting mixture;and isolating valacyclovir hydrochloride in form II from the mixture.

[0067] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form III including the step ofincubating valacyclovir hydrochloride in an atmosphere saturated withvapors of at least one of the following incubating solvents:isopropanol, ethanol, butanol, acetone, ethyl acetate, tetrahydrofurane,acetonitrile, methanol, and water. The valacyclovir hydrochloride can bein solid form or in solution in the incubating solvent.

[0068] In another aspect, the present invention relates to a method ofmaking valacyclovir in form IV including the step of incubatingvalacyclovir hydrochloride in an atmosphere having a relative humidityof about 100%.

[0069] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form V including the step of mixinga solution of valacyclovir hydrochloride in water with a lower aliphaticalcohol.

[0070] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form V including the step of mixinga solution of valacyclovir hydrochloride in water with iso-propanol.

[0071] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form VI including the step ofmixing a solution of valacyclovir hydrochloride in a first solventincluding water and an aliphatic monocarboxylic acid with a secondsolvent including a water-miscible ketone, particularly acetone, to forma suspension.

[0072] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form VI including the step ofmixing a solution of valacyclovir hydrochloride in a first solventincluding between about 30% and about 60% by volume of water, theremainder an aliphatic monocarboxylic acid, with a second solventincluding a water-miscible ketone in an amount that is about 2 to about5 times the volume of the first solvent.

[0073] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form VI including the step offiltering the solution of valacyclovir hydrochloride in a first solventincluding water and an aliphatic monocarboxylic acid; then mixing thesolution with a second solvent including a water-miscible ketone,preferably acetone, to form a suspension; and optionally, agitating thesuspension at a temperature less than about −10° C. and isolatingvalacyclovir hydrochloride in form VI from the suspension.

[0074] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form VII including the step ofmixing a solution of valacyclovir hydrochloride in a first solvent thatis essentially water with a second solvent that includes awater-miscible ketone, preferably acetone, to form a suspension; andoptionally further including the steps of agitating the suspension at atemperature less than about 10° C. and isolating valacyclovirhydrochloride in form VII from the suspension. A method of makingvalacyclovir hydrochloride in form I including the step of heatingvalacyclovir hydrochloride for about 2 hours at a temperature betweenabout 10° C. and about 130° C.

[0075] In another aspect, the present invention relates to a method ofmaking valacyclovir hydrochloride in form I including the steps ofdissolving valacyclovir hydrochloride in a solvent, and evaporating thesolution at a reduced pressure. Preferably, the solvent is a polarorganic solvent having 4 or fewer carbon atoms. Most preferably, thesolvent is an alcohol, preferably methanol.

[0076] In another aspect, the present invention relates to apharmaceutical composition including any one of valacyclovirhydrochloride in form I, II, IV, V, VI or VII.

[0077] In another aspect, the present invention relates to apharmaceutical composition including any mixture of two or more ofvalacyclovir hydrochloride in form I, II, IV, V, VI or VII.

DETAILED DESCRIPTION OF THE INVENTION

[0078] The present invention provides valacyclovir hydrochloride in newcrystalline forms I, II, IV, V, VI, and VII as well as admixtures of twoor more of these forms. The present invention also provides methods forpreparing valacyclovir hydrochloride in crystalline forms I, II, III,IV, V, VI, and VII as well as admixtures of two or more of these forms.

[0079] The present invention further relates to the solid state physicalproperties of these crystalline forms of valacyclovir hydrochloride asprepared by any of the methods of the present invention, as well as byother methods known to those skilled in the art.

[0080] As used herein, unless the context requires otherwise, the term“valacyclovir hydrochloride” includes anhydrous forms, hydrates,solvates, and all crystalline forms (both polymorphs andpseudopolymorphs), of valacyclovir hydrochloride. As used herein, theterm polymorphs is used broadly to include both polymorphs andpseudopolymorphs, i.e., all crystalline forms.

[0081] As used herein in connection with a measured quantity, the term“about” refers to that variation in the measured quantity as would beexpected by the skilled artisan performing the measurement andexercising a level of care commensurate with the objective of themeasurement and the precision of the measuring apparatus being used.

[0082] For the purposes of this specification, ambient or roomtemperature is from about 20° C. to about 25° C., elevated temperaturemeans above about 38° C., and cold temperature means below about −10° C.

[0083] All powder x-ray diffraction patterns were obtained by methodsknown in the art using a Scintag X′TRA X-ray powder diffractometer,equipped with a solid state Si(Li) detector thermoelectrically cooled,at scanning speed of 3° min.⁻¹. The scanning range was 2-40 degreestwo-theta. Copper radiation of □=1.5418° was used. The term x-raydiffraction “peaks” as used herein refers to x-ray diffraction“reflections” measured using an x-ray powder diffractometer. “Wet”samples (i.e. samples not dried) was analyzed as is. Dry samples weregently ground before analysis.

[0084] The differential thermal analysis (“DTA”) and thermogravimetricanalysis (“TGA”) curves presented herein were obtained by methods knownin the art using a DTG Shimadzu model DTG-50 (combined TGA and DTA). Theweight of the samples was about 9 to about 13 mg. The samples werescanned up to about 300° C. at a rate of 10° C./min. Sample chamberswere purged with nitrogen gas at a flow rate of 20 mL/min. Uncoveredstandard alumina crucibles were used.

[0085] Thermogravimetric analysis (TGA) is a measure of the thermallyinduced weight loss of a material. Thermogravimetric analysis (TGA) is athermal analysis technique well known in the art that detects andmeasures events that have associated with them a loss of mass, e.g. lossof water of hydration, as a function of temperature.

[0086] DTA denotes differential thermal analysis, a technique well knownin the art, that detects and measures thermal events in a sample, e.g.phase transitions, in which heat is either absorbed (endothermic) orliberated (exothermic).

[0087] Karl Fisher analysis, which is well known in the art, is alsoused to determine the quantity of water in a sample.

[0088] The term “water content” refers to the content of water basedupon the Loss on Drying method (the “LOD” method) as described in U.S.Pharmacopeia Forum, Vol. 24, No. 1, p. 5438 (January-February 1998), theKarl Fisher assay for determining water content or thermogravimetricanalysis (TGA). The term “equivalents of water” means molar equivalentsof water. All percentages referenced herein are by weight unlessotherwise indicated.

[0089] Those skilled in the art will also understand that the term“anhydrous” when used in reference to valacyclovir hydrochloridedescribes valacyclovir hydrochloride which is substantially free ofwater. Those skilled in the art will appreciate that the term “hydrate”when used in reference to valacyclovir hydrochloride describes acrystalline material having a water content of about 6-10% w/w.

[0090] When used in describing purity, percent refers to area percentdetermined by high-pressure liquid chromatography (HPLC), a methodwell-known to those skilled in the art, and is calculated according tothe equation:

% impuruty i=100×(area under peak i)/(Σ area of all peaks).

[0091] In one embodiment, the present invention provides valacyclovirhydrochloride in form I (“Form I”).

[0092] Valacyclovir hydrochloride in form I is characterized by an x-raydiffraction pattern with peaks (reflections) at about 3.7, 8.6, 10.6,a0.9, 13.3, 16.5, 24.0, and 27.2±0.2 degrees two-theta. FIG. 1 shows arepresentative x-ray powder diffraction pattern of valacyclovirhydrochloride in form I.

[0093] Valacyclovir hydrochloride in form I is also characterized by thethermal profile measured using the DTG-50 as discussed above, whichprovides both TGA and DTA thermograms as shown in FIG. 2. The DTAthermogram shows a broad endotherm below 125° C. The weight loss curvealso shows a weight loss step in this temperature range, with a measuredloss on drying value from about 6% to about 9% by weight. This LOD valuecorresponds to the stoichiometric amount of water of valacyclovirhydrochloride sesquihydrate and agrees with the water content determinedby the Karl-Fisher method.

[0094] In another embodiment, the present invention providesvalacyclovir hydrochloride in form II (“Form II”).

[0095] Valacyclovir hydrochloride in form II is characterized by anx-ray diffraction pattern with peaks (reflections) at about 6.6, 11.5,17.3, 19.0, 21.5, 26.3, 27.4 and 28.0±0.2 degrees two theta. FIG. 3shows a representative x-ray powder diffraction pattern of valacyclovirhydrochloride in form II.

[0096] Valacyclovir hydrochloride in form II can also be characterizedby differential thermal analysis (DTA), as shown in FIG. 4, which showsan endothermic peak at 211° C. followed by an exothermic peak.

[0097] Valacyclovir hydrochloride in form III (“Form III”) is the priorart anhydrous form of valacyclovir hydrochloride disclosed in U.S. Pat.No. 6,107,302.

[0098] In one embodiment, the present invention provides a method forpreparing valacyclovir hydrochloride in form III.

[0099] In another embodiment, the present invention providesvalacyclovir hydrochloride in form IV (“Form IV”).

[0100] Valacyclovir hydrochloride in form IV is characterized by anx-ray diffraction pattern with peaks (reflections) at about 3.6, 10.7,15.1, 26.9, and 28.1±0.2 degrees two-theta. Fig. @@ shows arepresentative x-ray diffraction pattern for valacyclovir hydrochloridein form IV.

[0101] Valacyclovir hydrochloride in form IV can be furthercharacterized by the thermal thermal analysis using the DTG-50 asdiscussed above, which provides both TGA and DTA thermograms as shown inFIG. 5. The DTA thermogram shows two broad endothermic peaks at about45° C. and 100° C. The weight loss curve shows two weight loss steps inthe temperature range of up to about 130° C. The loss on drying (LOD)value in this temperature range is about 9.7%. This corresponds to thestoichiometric amount of water of valacyclovir hydrochloride dihydrateand agrees with the water content determined by the Karl-Fisher method.

[0102] Form IV can include higher amounts of solvents, up to about 15%.

[0103] In still another embodiment, the present invention providesvalacyclovir hydrochloride in form V.

[0104] Valacyclovir hydrochloride in form V is characterized by x-rayreflections (peaks) at about 6.7°, 15.7°, 16.2°, and 22.6°±0.2 degreestwo-theta.

[0105] Valacyclovir hydrochloride in form V of the present invention canbe further characterized by additional x-ray reflections (peaks) atabout 3.4°, 9.5°, 13.5°, 21.9°, 27.2°, and 28.60+0.2° two-theta. FIG. 12shows a representative x-ray powder diffraction pattern of valacyclovirhydrochloride in form V.

[0106] Valacyclovir hydrochloride in form V can be further characterizedby DTA and TGA measurements as shown in FIG. 13. DTA thermograms ofvalacyclovir hydrochloride in form V of the present invention exhibit abroad endothermic peak at about 95° C. and a sharp endothermic peak atabout 180° C. The weight loss curve (TGA) shows a weight loss of betweenabout 5% and about 7% over the temperature range between about 25° C.and about 130° C.

[0107] In another embodiment, the present invention providesvalacyclovir hydrochloride in form VI (“Form VI”).

[0108] Valacyclovir hydrochloride in form VI is characterized by X-raydiffraction reflections (peaks) at about 6.2°, 9.2°, 12.1°, 20.2° and25.7°±0.2° 2θ. FIG. 14 shows a representative x-ray powder diffractionpattern for valacyclovir hydrochloride in form VI.

[0109] In yet another embodiment, the present invention providesvalacyclovir hydrochloride in form VII (“Form VII”).

[0110] Valacyclovir hydrochloride in form VII is characterized by x-rayreflections (peaks) at about 3.5°, 10.3°, 13.6°, 26.2° and 28.1±0.2° 2θ.FIG. 15 shows a representative x-ray powder diffraction pattern forvalacyclovir hydrochloride in form VII.

[0111] The novel crystalline forms (polymorphs and pseudopolymorphs) ofvalacyclovir hydrochloride of the present invention can be prepared byany one or more of the methods described below, each of which representsan embodiment of the present invention. Three methods used in particularembodiments are: (1) the slurry method, also known as the triturationmethod; (2) the vapor incubation method; and (3) the precipitationmethod. Also provided are thermal and evaporative methods for makingvalacyclovir hydrochloride in form I.

[0112] In particular embodiments, the crystalline forms of valacyclovirhydrochloride of the present invention can be made by a slurry methodthat includes the step of suspending, or “slurrying”, a quantity ofvalacyclovir hydrochloride in a slurry solvent, preferably with the aidof mechanical agitation.

[0113] Examples of procedures for forming polymorphs by the slurrymethod are provided in examples 1 to 21. The amount of slurry solventcan vary between about 5 mL and about 15 mL, preferably between about 8mL and about 12 mL, most preferably about 10 mL per gram of valacyclovirhydrochloride. The slurry is agitated for a time sufficient to achievethe desired transformation. Agitation may be provided by any means knownto those skilled in the art, for example by using a magnetic stirrer ora propeller-type stirrer inserted into the solution. It was surprisinglyfound that polymorph formation by the slurry method can be moreefficient when a magnetic stirrer rather than a propeller was used topromote stirring.

[0114] The extent of transformation during agitation can be monitoredby, for example, removing an aliquot of the slurry, separating thesolid, and analyzing the crystal form of the solid by, for example,x-ray diffraction.

[0115] Valacyclovir hydrochloride in the resulting crystalline form canbe isolated from the slurry by any means known in the art. For example,filtration (gravity or suction) or centrifugation may be used, tomention just two.

[0116] If desired, or if required to make a particular polymorph, theproduct isolated from the slurry method can be dried at atmosphericpressure, or it can be dried at reduced pressure.

[0117] In other embodiments, the crystal forms of the present inventioncan be made by a vapor incubation method. In the vapor incubationmethod, valacyclovir hydrochloride is exposed to an atmosphere saturatedor nearly saturated with vapors of an incubating solvent. Valacyclovirhydrochloride can be exposed as solid particles, preferably in a thinlayer to maximize the surface exposed to vapors of the incubatingsolvent, or it can be exposed as its solution in the incubating solvent.Vapor incubation can be performed by placing a quantity of a solid formof valacyclovir hydrochloride in a small open container or by incubatingvalacyclovir hydrochloride in a solvent atmosphere in a closedcontainer.

[0118] Preferably, the sample is incubated for a time ranging from about7 to about 32 days. When the incubating solvent is water, the degree ofchamber humidity may be regulated using salts or salt solutions such aspotassium sulphate, zinc nitrate, potassium acetate, ammonium sulphate,as is known in the art.

[0119] If desired, of if required to make a particular polymorph,product from the incubation method can be dried at atmospheric pressure,or it can be dried at reduced pressure.

[0120] Examples of procedures for preparing crystalline forms ofvalacyclovir hydrochloride by the vapor incubation method are providedin examples 22-27.

[0121] In still other embodiments, the crystal forms of the presentinvention can be made by a precipitation method that includes the stepof mixing, with mechanical agitation, a solution of valacyclovirhydrochloride in a first solvent with a second solvent to form asuspension. Preferably, valacyclovir hydrochloride is practicallyinsoluble in the second solvent.

[0122] Examples of procedures for preparing crystalline forms ofvalacyclovir hydrochloride by the precipitation method are provided inexamples 28 to 32.

[0123] The concentration of valacyclovir hydrochloride in first solventcan vary from between about 30 to about 65%. The ratio of the volume ofsecond solvent to solution can vary between about 3:1 to about 15:1,relative to the volume of solution in first solvent

[0124] Mechanical agitation can be provided by any means known in theart, for example magnetic stirrers or paddle-, propeller- orturbine-type stirrers, to mention just a few. The skilled artisan willknow to select the means of agitation depending on, among other things,the size and geometry of the vessel being used and the viscosity of thesolution and suspension.

[0125] In preferred embodiments that incorporate the precipitationmethod, the method includes the step of agitating the suspension forabout 2 to about 24 hours at a temperature less than about −10° C.

[0126] Valacyclovir hydrochloride in the resulting crystal form can beisolated from the suspension by any means known in the art. For example,filtration (gravity or suction) or centrifugation can be used, tomention just two. After isolation, the valacyclovir hydrochloride in theresulting crystal form can be dried at atmospheric pressure or atreduced pressure (vacuum), both methods of which are known in the art.

[0127] It will be understood by those of skill in the art that othermethods may also be used to produce the crystalline forms disclosedherein.

[0128] In one embodiment, the present invention provides a thermalmethod for making valacyclovir hydrochloride in form I including thestep of heating valacyclovir hydrochloride for about 1 to about 3 hours,preferably about 2 hr, at a temperature between about 30° C. and about60° C., preferably 40° C. Preferably, the material is dried undervacuum. The product so obtained is valacyclovir hydrochloride in form Iaccording to x-ray diffraction analysis.

[0129] In another embodiment, the present method provides an evaporativemethod for making valacyclovir hydrochloride in form I. In theevaporative method, valacyclovir hydrochloride is dissolved in an amountof solvent (about 200 mL to about 300 mL, preferably about 250 mL,solvent per gram of valacyclovir hydrochloride) at 40° C. The solvent isevaporated, preferably at reduced pressure, to yield valacyclovirhydrochloride in form I. Polar organic solvents, especially alcohols,having 4 or fewer carbon atoms are preferred for use in the evaporationmethod. Methanol is a particularly preferred solvent for use in thismethod.

[0130] In yet another embodiment, the present invention provides aslurry method for making valacyclovir hydrochloride in form I, includingthe step of suspending valacyclovir hydrochloride as a slurry in aslurry solvent, and optionally, the further steps of isolatingvalacyclovir hydrochloride in form I from the slurry and drying at atemperature between about 50° C. and about 70° C. The slurry solvent forpreparing valacyclovir hydrochloride in form I is a non-polar organicsolvent, preferably selected from ethyl acetate, acetone, methyl ethylketone, dioxane, methylene chloride, t-butyl methyl ether, andtetrahydrofurane.

[0131] In another embodiment, the present invention provides a slurrymethod for making valacyclovir hydrochloride in form II, including thestep of suspending valacyclovir hydrochloride as a slurry in a slurrysolvent selected from isopropyl alcohol, 1-butanol, acetonitrile, methylethyl ketone, ethyl acetate, ethanol, acetone and toluene.

[0132] The slurry can be agitated with any stirrer known in the art,preferably a propeller-type stirrer, and most preferably, a magneticstirrer. The step of suspending valacyclovir hydrochloride as a slurryis performed for about 20 to about 28, preferably about 24 hours.

[0133] In another embodiment, the present invention provides a slurrymethod of making valacyclovir hydrochloride in form II including thesteps of suspending valacyclovir hydrochloride as a slurry in a slurrysolvent at reflux; adding methanol to the slurry; refluxing theresultant mixture; and isolating valacyclovir hydrochloride in form IIfrom the mixture.

[0134] In another embodiment, the present invention provides a slurrymethod for making valacyclovir hydrochloride form II, including thesteps of: suspending valacyclovir hydrochloride as a slurry in a tolueneat reflux; adding methanol to the slurry; further refluxing theresulting slurry in mixed solvents; and isolating valacyclovirhydrochloride in form II from the resulting slurry in mixed solvents.

[0135] Valacyclovir hydrochloride in form II can be isolated from theslurry by cooling the slurry to room temperature and collecting thecrystals by any means known in the art.

[0136] In a particular embodiment, isolated crystals are dried undervacuum, i.e. at a pressure less than abut 500 mm Hg at 50° C.Alternatively, the step of drying the crystals is performed atatmospheric pressure at 60° C.

[0137] In another embodiment, the present invention provides a methodfor making valacyclovir hydrochloride form IV, including the steps ofincubating valacyclovir hydrochloride in an atmosphere saturated withvapors of at least one of the following incubating solvents:isopropanol, ethanol, butanol, acetone, ethyl acetate, letrahydrofurane,acetonitrile, methanol, and water. The valacyclovir hydrochloride can beincubated as a solid or as a solution. Acetonitrile is a preferredincubating solvent when valacyclovir hydrochloride in solid form isused.

[0138] In a particular embodiment of the vapor incubation method,valacyclovir hydrochloride is dissolved in hot methanol and incubated inan atmosphere saturated with vapors of an incubating solvent in a closedcontainer for from about 25 to about 40 days, preferably 32 days. Theincubating solvent is preferably selected from acetone, ethyl acetate,tetrahydrofuran, ethanol, or butanol.

[0139] In another particular preferred embodiment, the present inventionprovides a process for preparing valacyclovir hydrochloride in form IV,including the steps of incubating valacyclovir hydrochloride in form IIin an atmosphere saturated with water at 100% humidity.

[0140] In another embodiment, the present invention provides a methodfor making valacyclovir hydrochloride in forms I and IV by theprecipitation method. Valacyclovir hydrochloride is dissolved in a firstsolvent, preferably about 6 mL first solvent per gram of valacyclovirhydrochloride, at about 20° C. to about 30° C., preferably about 25° C.The solution in first solvent is mixed with a second solvent, in avolume amount about 10 to about 30, preferably about 17 times the volumeof first solvent. The resulting suspension is stirred for about 1 hourand filtered to recover precipitate wet cake. Optionally, theprecipitate wet cake is dried in vacuo at 40° C.

[0141] Water is the preferred first solvent. Polar organic solvents,protic or aprotic, are useful as second solvents. Preferred secondsolvents are acetonitrile, butanol, and acetone. Optionally, the secondsolvent can be used to form the initial solution and precipitation ofthe polymorph effected by addition of first solvent.

[0142] In another embodiment, the present invention provides a method ofmaking valacyclovir hydrochloride in form V by the precipitation method,for example, by mixing a solution of valacyclovir hydrochloride in afirst solvent with a second solvent that is an alcohol, preferablyisopropanol.

[0143] The solution is in a first solvent that includes water and,optionally, a water-miscible organic solvent such as acetic acid, awater-miscible ketone, or, preferably, an alcohol. When a ketone isused, acetone is the preferred ketone. When alcohol is used, isopropanolis the preferred alcohol. Preferably, water is the major constituent ofthe solvent. Most preferably, the first solvent is water.

[0144] Preferably, the solution in the first solvent contains one partby weight valacyclovir hydrochloride and about 2 to about 6 parts byweight solvent. The solution can be made by, for example, dissolving thedesired amount of valacyclovir hydrochloride in about 2 to about 6 partsby weight solvent. The valacyclovir hydrochloride can be made by anymeans known in the art, or it can be generated in situ fromt-butoxycarbonyl valacyclovir (t-BOC Val), in which the nitrogen of thevaline residue attached to the acyclovir moiety bears a butoxycarbonylgroup.

[0145] When valacyclovir hydrochloride is generated in situ in apreferred embodiment, about 3 to about 7, preferably about 5,equivalents of hydrogen chloride, dissolved in a suitable vehicle, areadded, preferably slowly to maintain temperature control, to asuspension of a protected valacyclovir (e.g., t-BOC valacyclovir) in asuitable solvent mentioned above. The vehicle can be any of thosesolvents mentioned above. Preferably, the vehicle and solvent are bothwater.

[0146] After addition of the hydrogen chloride, the mixture is stirredat a temperature below about 40° C., preferably at about 20° to 25° C.,until the mixture essentially becomes a solution that can be roily orturbid. The mixture is then cooled to a temperature below about 10° C.,preferably at about 0° C., and mixed with an alcohol, preferablyisopropanol (20 to 30 volumes based on the volume of solvent used) toform a suspension. Preferably, the suspension is stirred for at leastabout one-half hour at this temperature. The suspension can be stirredat a temperature below about 4° C. for a period of time, for exampleabout 8 to about 18 hours.

[0147] Valacyclovir hydrochloride in form V can be isolated from thesuspension by any means known in the art. For example, isolation can beby filtration (gravity or suction) or by centrifugation, to mention justtwo.

[0148] Typically, valacyclovir hydrochloride in form V prepared asdescribed above will have a chemical purity of at least about 97%.

[0149] In another embodiment, the present invention also provides amethod of making valacyclovir hydrochloride in form VI by theprecipitation method. Valacyclovir hydrochloride is dissolved in a firstsolvent including an aliphatic monocarboxylic acid and water. Thesolution is optionally filtered and the filtrate then combined with asecond solvent that is a water-miscible ketone to form a suspensionwhich is then cooled. Aliphatic monocarboxylic acids have the formulaRCO₂H wherein R is a linear or branched alkyl group having 1 to 6 carbonatoms. The preferred aliphatic monocarboxylic acid is acetic acid, andthe preferred water-miscible ketone is acetone.

[0150] It is preferred to slowly combine the filtered solution in thefirst solvent (filtrate_ and the second solvent. Slowly combining meansadding small amounts of filtrate, preferably dropwise, over a period oftime, preferably from one-half hour to 3 three hours. It is especiallypreferred to add the filtrate dropwise over about an hour.

[0151] Valacyclovir hydrochloride in form VI can be recovered from thesuspension by any means known in the art; for example, isolation can beby filtration (gravity or suction) or by centrifugation, to mention justtwo.

[0152] In another embodiment, the present invention provides a method ofmaking valacyclovir hydrochloride in form VI by the precitation method.For example, BOC-valacyclovir is dissolved in acetic acid and mixed withhydrochloric acid and water. The solution is then filtered and thefiltrate added dropwise to acetone to form a suspension which is thencooled.

[0153] It is preferred to add one part by weight BOC-valacyclovir toabout 2-5, preferably about 3, parts by weight of acetic acid. Themixture is stirred at an elevated temperature (over 38° C.), preferablyabout 50° C., to dissolve the solids and subsequently cooled to ambientor room temperature, around 25° C. The mixture is maintained under anatmosphere of inert gas, preferably argon. A mixture of about 1 parthydrochloric acid to about 1-4, preferably 2, parts by weight water isthen added dropwise over about 1 hour to the mixture of valacylovir andacetic acid.

[0154] After being stirred at ambient temperature for about 1 to 4hours, preferably about 3 hours, the solution is filtered and theresultant filtrate is added over a period of time, preferably about 1hour, to an amount of acetone that is about 2 to 5 times the volume offiltrate. The suspension is then stirred first for about 1 to 4 hours,preferably 2 hours, at ambient temperature and then for a longer time,12 to 18 hours, preferably 14 hours, at a cold temperature below −10°C., preferably −15° C.

[0155] Typically, valacyclovir hydrochloride in form VI prepared asdescribed above will have a chemical purity of at least about 98%purity.

[0156] In another embodiment, the present invention also provides amethod of making valacyclovir hydrochloride in form VII by theprecipitation method, including the steps of: dissolving valacyclovirHCl in first solvent that is water, filtering the solution, combiningthe filtered solution with a second solvent that is a water-miscibleketone to obtain a suspension, and then cooling and isolatingvalacyclovir hydrochloride in form VII. Acetone is the preferredwater-miscible ketone.

[0157] Valacyclovir hydrochloride in form VII can be isolated from thesuspension by any means known in the art. For example, isolation can beby filtration (gravity or suction) or by centrifugation, to mention justtwo.

[0158] Typically, one part by weight valacyclovir hydrochloride isdissolved with about 3-5, preferably about 4, parts by weight of water.The solution is stirred at an elevated temperature above about 38° C.,preferably about 40° C., to dissolve the solids. The solids are thenfiltered. The resultant filtrate is added to an amount of awater-miscible ketone, preferably acetone, equal to about 2 to 6 timesthe volume of filtrate to form a suspension. The suspension is thenstirred first for about 1 to about 4 hours, preferably 2 hours, at atemperature between about 20 and 25° C., preferably about 20° C., andthen for a longer time, about 10 to 18 hours, preferably about 12 hours,at a cold temperature below about −10° C., preferably −15° C.

[0159] Typically, valacyclovir hydrochloride in form VII prepared asdescribed above has a chemical purity of about 99%.

[0160] In still another embodiment, the present invention provides amethod for making valacyclovir hydrochloride monohydrate including thesteps of contacting a solution of valacyclovir hydrochloride in waterwith about two to about four times the volume thereof of iso-propanol toform a suspension, stirring the suspension for a stirring period at atemperature below about −10° C., isolating the solid, and drying thesolid at reduced pressure to constant weight. The contacting ispreferably by mixing with mechanical agitation.

[0161] Preferably, the solution and IPA are contacted at a temperaturebetween about 30° C. and about 50° C., preferably at about 40° C.Preferably the temperature during the stirring period is about −15° C.The solid can be isolated from the suspension by any means known in theart, for example filtration.

[0162] Methods of Use, Formulations, Dosages

[0163] Valacyclovir hydrochloride may be formulated into a variety ofpharmaceutical compositions and dosage forms that are useful in treatingpatients afflicted with viral infections, particularly infections causedby the herpes group of viruses.

[0164] In one embodiment, the present invention relates topharmaceutical compositions including valacyclovir hydrochloride in atleast one of forms I, II, IV, V, VI or VII. In addition to the activeingredient(s), valacyclovir hydrochloride pharmaceutical compositions ofthe present invention may contain one or more excipients. Excipients areadded to the composition for a variety of purposes.

[0165] Diluents increase the bulk of a solid pharmaceutical compositionand may make a pharmaceutical dosage form containing the compositioneasier for the patient and caregiver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.AVICEL®, microfine cellulose, lactose, starch, pregelitinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

[0166] Solid pharmaceutical compositions that are compacted into adosage form like a tablet may include excipients whose functions includehelping to bind the active ingredient and other excipients togetherafter compression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.KLUCEL®), hydroxypropyl methyl cellulose (e.g. METHOCEL®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinizedstarch, sodium alginate and starch.

[0167] The dissolution rate of a compacted solid pharmaceuticalcomposition in the patient's stomach may be increased by the addition ofa disintegrant to the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-DI-SOL®, PRIMELLOSE®)), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. KOLLIDON®), POLYPLASDONE®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) andstarch.

[0168] Glidants can be added to improve the flow properties ofnon-compacted solid compositions and improve the accuracy of dosing.Excipients that may function as glidants include colloidal silicondixoide, magnesium trisilicate, powdered cellulose, starch, talc andtribasic calcium phosphate.

[0169] When a dosage form such as a tablet is made by compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl famarate,stearic acid, talc and zinc stearate.

[0170] Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid ethyl maltol, and tartaric acid.

[0171] Compositions may also be colored using any pharmaceuticallyacceptable colorant to improve their appearance and/or facilitatepatient identification of the product and unit dosage level.

[0172] Selection of excipients and the amounts to use may be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

[0173] The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable route in any given case willdepend on the nature and severity of the condition being treated, themost preferred route of the present invention is oral. The dosages maybe conveniently presented in unit dosage form and prepared by any of themethods well-known in the pharmaceutical arts.

[0174] Dosage forms include solid dosage forms like tablets, powders,capsules, suppositories, sachets, troches and lozenges as well as liquidsyrups, suspensions and elixirs. An especially preferred dosage form ofthe present invention is a tablet.

[0175] Tablets, capsules, lozenges and other unit dosage formspreferably contain modafinil in a dosage level of from about 50 to about300 mg, more preferably from about 100 mg to about 200 mg.

[0176] The currently marketed form of valacyclovir (VALTREX®) containsvalacyclovir hydrochloride equivalent to 500 mg valacyclovir and theinactive ingredients carnauba wax, colloidal silicon dioxidecrospovidone, FD&C Blue No. 2 Lake, hydroxypropyl methylcellulose,magnesium stearate, microcrystalline cellulose polyethylene glycol,polysorbate 80, povidone and titanium dioxide.

[0177] The function and advantage of these and other embodiments of thepresent invention will be more fully understood from the examples below.The following examples demonstrate the preparation of variouscrystalline forms of valacyclovir hydrochloride by the slurry method(examples 1 to 21), the vapor incubation method (examples 22 to 27), andthe precipitation method (examples 28 to 32). Preparation of form I bythe heating and evaporative method are also illustrated in examples 33and 34 respectively. These examples are intended to illustrate thebenefits of the present invention, but are not intended to limit thescope of the invention.

EXAMPLES

[0178] Preparation of Crystalline Forms of Valacyclovir Hydrochloride bythe Slurry Method:

Example 1

[0179] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in ethyl acetate (10 mL) for 24 hours. The mixturewas filtered and the isolated solid was dried at 60° C. for 24 hours togive valacyclovir hydrochloride form I.

Example 2

[0180] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in acetone (10 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form I.

Example 3

[0181] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in methyl ethyl ketone (MEK) (15 mL) for 24 hours.The mixture was filtered and the isolated solid was dried at 60° C. for24 hours to give valacyclovir hydrochloride form I.

Example 4

[0182] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in dioxane (15 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form I.

Example 5

[0183] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in methylene chloride (15 mL) for 24 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form I.

Example 6

[0184] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in t-butyl methyl ether (15 mL) for 24 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form I.

Example 7

[0185] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in t-butyl methyl ether (20 mL) for 24 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form 1.

Example 8

[0186] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in tetrahydrofurane (THF) (20 mL) for 24 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form I.

Example 9

[0187] Valacyclovir hydrochloride (1 g) was suspended in slurry with amagnetical stirrer at ambient temperature in isopropyl alcohol (10 mL)for 24 hours. The mixture was filtered and the isolated solid was driedat 60° C. for 24 hours to give valacyclovir hydrochloride form II.

Example 10

[0188] Valacyclovir hydrochloride (1 g) was suspended in slurry with amechanical stirrer at ambient temperature in Isopropyl alcohol (15 mL)for 24 hours. The mixture was filtered and the isolated solid was driedat 60° C. for 24 hours to give valacyclovir hydrochloride form II.

Example 11

[0189] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in 1-butanol (10 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form II.

Example 12

[0190] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in 1-butanol (20 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form II.

Example 13

[0191] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in acetonitrile (25 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form II.

Example 14

[0192] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in methyl ethyl ketone (20 mL) for 22 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form II.

Example 15

[0193] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in ethyl acetate (20 mL) for 22 hours. The mixturewas filtered and the isolated solid was dried at 60° C. for 24 hours togive valacyclovir hydrochloride form II.

Example 16

[0194] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in ethanol absolute (15 mL) for 18 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form II.

Example 17

[0195] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in Isopropyl alcohol (15 mL) for 24 hours. Themixture was filtered and the isolated solid was dried at 60° C. for 24hours to give valacyclovir hydrochloride form II.

Example 18

[0196] Valacyclovir hydrochloride (1 g) was suspended in slurry atambient temperature in acetonitrile (20 mL) for 24 hours. The mixturewas filtered and the isolated solid was dried at 60° C. for 24 hours togive valacyclovir hydrochloride form II.

Example 19

[0197] Valacyclovir hydrochloride (1 g) was suspended in slurry atreflux temperature in acetone (11 mL) for 24 hours. The mixture wasfiltered and the isolated solid was dried at 60° C. for 24 hours to givevalacyclovir hydrochloride form II.

Example 20

[0198] Valacyclovir hydrochloride (5 g) was placed in a three neck flaskequipped with a Dean-Stark Trap. Toluene (40 mL) was then added and theslurry was heated to reflux temperature. At reflux temperature, toluene(160 mL) and methanol (20 mL) were added. Thirty mL of the solvent weredistilled and more methanol added (30 mL). The reaction mixture wasrefluxed for 45 minutes and the slurry was cooled to ambienttemperature, filtered under reduced pressure and dried according to 2different procedures: (1) by vacuum oven at 50° C. for 24 hours; and,(2) atmospheric oven at 60° C. for 24 hours. Both samples werevalacyclovir hydrochloride form II.

Example 21

[0199] General procedure: two grams of valacyclovir hydrochloride werestirred in the desired refluxing solvent (200 mL) for 1 hr. The slurrywas cooled to room temperature (ca. 25° C.) over a period of about 1 hr.The suspension so obtained was filtered to obtain wet cake. A portion ofthe wet cake was analysed by x-ray diffraction to determine thepolymorphic form. The wet cake was dried in vacuo at 40° C. The watercontent and polymorphic (crystal) form of the product after the dryingstep were determined.

[0200] The general procedure was repeated with various solvents. Thetable below lists the polymorph and moisture content obtained with thevarious solvents, with (d) and without (w) drying. Exp. Solvent X-RayResults 137-01 w IPA IV + III 137-02 d IV + II  138-01 w EtOH IV 138-02d I 139-01 w Acetone IV 139-02 d I 140-01 w THF IV 140-02 d I 141-01 wEtOH/H₂O (100:1) IV >>>> III 141-02 d I 142-01 w EtOH/H₂O (100:2) IV142-02 d I 149-01 d EtOH/H₂O (100:2) IV 143-01 w EtOH/H₂O (100:5)IV >>>> III 150-01 d EtOH/H₂O (100:5) I 144-01 w IPA/H₂O (100:3) I144-02 d I + II 145-01 w IPA/H₂O (100:8) IV 145-02 d I 148-01 w BuOH III148-02 d II 155-01 w Dioxane I 155-02 d I 161-01-w MEK IV 161-02-d I

[0201] Preparation of Crystalline Forms of Valacyclovir Hydrochloride bythe Vapor Incubation Method:

Example 22

[0202] Valacyclovir hydrochloride dry was incubated in a solventatmosphere of acetonitrile for 1 week. The wet sample was then analyzedby powder X-ray crystallography and shown to be valacyclovirhydrochloride form II.

Example 23

[0203] Valacyclovir hydrochloride form I was incubated in controlledhumidity cell having a relative humidity of 100% for 1 week to yieldvalacyclovir hydrochloride form IV dihydrate.

Example 24

[0204] Valacyclovir hydrochloride was dissolved in a minimum of hotmethanol. The methanol solution was incubated in solvent saturatedatmosphere for 32 days in a closed bottle. After 32 days the compoundswere crystallized. The procedure was repeated with three differentincubating solvents: acetone, ethyl acetate and tetrahydrofuran. In eachcase, the product obtained was valacyclovir hydrochloride in form III.

Example 25

[0205] Valacyclovir hydrochloride was dissolved in a minimum of hotmethanol. The methanol solution was incubated in butanol atmosphere for32 days in a closed bottle. After 32 days the compounds werecrystallized, yielding valacyclovir hydrochloride form III. Theprocedure was repeated with two different incubating solvents: ethanolabs., butanol. The product obtained was valacyclovir hydrochloride inform III.

Example 26

[0206] Valacyclovir hydrochloride dry was incubated in a solventatmosphere of ethanol for 1 week. Then the wet sample was analyzed andshown to be valacyclovir hydrochloride form III.

Example 27

[0207] Valacyclovir hydrochloride dry was incubated in a solventatmosphere of methanol for 1 week. Then the wet sample was analyzed andshown to be valacyclovir hydrochloride form III.

[0208] Preparation of Crystalline Forms of Valacyclovit Hydrochloride bythe Precipitation Method:

Example 28

[0209] General Procedure: Three Grams of Valacyclovir hydrochloride weredissolved in 18 mL of first solvent at about 25° C. The solution wasstirred and 300 mL of second solvent were added to the solution. Asuspension of a white solid precipitate of valacyclovir hydrochloridewas formed.

[0210] The suspension was stirred 1 hr and filtered to recover wet cakeprecipitate. A portion of the wet cake precipitate was analysed by x-raydiffraction to determine the polymorphic form. The wet cake was dried invacuo at 40 C. The water content and polymorphic form of the driedmaterial were determined.

[0211] Table A gives the results obtained with several second solventswhen water was the first solvent. Table B gives the results obtainedwith water as the second solvent. A Exp. Solvent Water content (%) X-RayResults 147-01 w ACN IV 147-02 d 9.22 I 152-01 w BuOH IV 152-02 d 5.74 I154-01 w Acetone IV

[0212] B Exp. Solvent Water content (KF, %) X-Ray Results 151-01 w ACNIV 151-02 d 6.85 I 153-01 w BuOH IV 153-02 d 8.72 I

Example 29

[0213] Reagents: t-BOC Valacyclovir, F.W. 424.45 4.5 g (10.5 mmol)Hydrochloric acid, 37%, F.W. 36.46 4 mL (47.3 mmol) Water, F.W. 18.02 19mL

[0214] Thirty-seven percent hydrochloric acid (4 mL) was added dropwise,during 10 min to a suspension of t-BOC-valacyclovir (4.5 g) in Water (19mL) at 20-25° C. The reaction mixture was stirred for about 5 h at20-25° C., cooled with ice water, followed by addition of IPA to thismixture to give a white precipitate. The suspension was stirred forabout 1 h at T<10° C. (ice water bath) and kept at 4° C. overnight. Theprecipitate was filtered off, washed with cold IPA (20 mL) and dried togive valacyclovir HCl in form V(2.6 g, 68%), 97.7% pure by RPLC, 4.07%of D-isomer.

Example 30

[0215] Reagents: t-BOC Valacyclovir F.W. 424.45 9.0 g (21.0 mmol)Hydrochloric acid, 37%, F.W. 36.46 8 mL (94.6 mmol) Water, F.W. 18.02 22mL

[0216] A mixture of t-BOC-valacyclovir (9.0 g, 21 mmol) and water (22mL) was stirred for about 20 min. to obtain a fine suspension. 37%hydrochloric acid (8 mL) was added dropwise to this suspension at 20-25°C., the reaction mixture was stirred for about 3.5 h at 20-25° C.,cooled with ice water, followed by addition of IPA (500 mL) to give awhite precipitate. The suspension was stirred for about 1 h at T<10° C.(ice water bath) and kept at 4° C. overnight. The white precipitate wasfiltered off, dried under reduced pressure to give valacyclovir HCl inform V (7.0 g, 92%), 97.9% pure by HPLC, 4.0% of D-isomer.

Example 31

[0217] A 250-mL double-jacketed reactor was charged withBOC-valacyclovir (15.0 g) and acetic acid (45.0 g) and filled withargon. The obtained mixture was stirred at 50° C. to completedissolution of all solids and cooled to 25° C. A mixture of 37%hydrochloric acid (13.9 g) and water (30.0 g) was added dropwise overone hour and the solution was stirred for 3 hours at 20-25° C. Thereaction mixture was filtered and the filtrate was added dropwise at 25°C. over a period of one hour to acetone (188 g). The suspension was thenstirred for 2 hours at 25° C. and then at 14 hours at −15° C. Theprecipitate was filtered off, washed on the filter with cold acetone (28g) to obtain 19.1 g of wet product which was dried under reducedpressure at 25° C. to a constant weight to give 10.8 g (84.9%) ofvalacyclovir hydrochloride in form VI with 98.67% purity by HPLC. Boththe wet and dry products contain valacyclovir hydrochloride in form VI,as characterized by X-ray powder diffraction.

Example 32

[0218] A 50-mL reactor was charged with a crude valacyclovir HCL (8.8 g)and water (35.2 g). The obtained mixture was stirred at 40° C. tocomplete dissolution of all solids and a solution was filtered. Thefiltrate was added to acetone (132 g) at 40° C., a suspension wasstirred for 2 hours at 20° C. and 12 hours at −15° C. The precipitatedsolid was filtered off, washed on the filter with cold acetone (20 g) togive valacyclovir hydrochloride form VII, as characterized by X-raypowder diffraction. This method produced valacyclovir hydrochloride inform VII with 99% purity by HPLC.

[0219] Preparation of Valacyclovir Form I by the Thermal Method:

Example 33

[0220] Valacyclovir hydrochloride form IV was dried to constant atreduced pressure at 40-50° C. Analysis of the sampel showed it to beform I.

[0221] Preparation of Valacyclovir Form I by the Evaporative Method:

Example 34

[0222] Two grams of valacyclovir hydrochloride were dissolved in 250 mLof methanol at 40° C. The methanol was evaporated at 40° C. underreduced pressure to obtain form I.

[0223] Preparation of Valacyclovir Monohydrate by a Precipitation Method

Example 35

[0224] A 1 L reactor was charged with crude valacyclovir hydrochloride(180 g) and water (720 g). The mixture was heated to and stirred atabout 40° C. to effect dissolution of the solids. The solution wasfiltered and the filtered solution was added to 2-propanol (2700 g) in a6L double-jacketed reactor at 40° C. to form a suspension. Thesuspension formed was stirred for 2 hours at 25° C. and the 4 hours at−15° C. The precipitated solids were collected by filtration, washedwith cold 2-propanol (1440 g) and dried to constant weight under reducedpressure to yield 148.5 g (82.5%) of valacyclovir monohydrate with 99.52area-% purity by HPLC, assay 96.7% by HClO₄ titration assay, assay 95.0%by AgNO3 titration. The water content (Karl-Fisher) of the product was3.45%. The loss on drying (TGA) was 4.5%.

We claim:
 1. Valacyclovir hydrochloride form I.
 2. Valacyclovirhydrochloride form I of claim 1 characterized by x-ray diffractionreflections at about 3.7°, 8.6°, 10.6°, 10.9°, 16.5°, 24.0° and27.2°±0.2° 2θ.
 3. Valacyclovir hydrochloride form I of claim 2 furthercharacterized by x-ray diffreaction reflections at about 9.5°, 10.9°,20.1°, 21.4°, and 26.7°±0.2° 2θ.
 4. Valacyclovir hydrochloride form I ofclaim 2 further characterized as having a weight loss of between about6% and about 9% as measured by thermogravimetric analysis over thetemperature range between about 25° C. and about 125° C.
 5. Valacyclovirhydrochloride in form I of claim 1 characterized by the x-raydiffraction pattern substantially as shown in FIG.
 1. 6. Valacyclovirhydrochloride sesquihydrate.
 7. Valacyclovir hydrochloride form II. 8.Valacyclovir hydrochloride form II of claim 7 characterized by x-raydiffraction reflections at about 6.6°, 19.0°, 21.5°, 27.4°, and28.5°±0.2° 2θ.
 9. Valacyclovir hydrochloride form II of claim 8 furthercharacterized by x-ray diffraction reflections at about 9.2°, 15.6°, and26.3°±0.2°θ2θ.
 10. Valacyclovir hydrochloride in form II of claim 8further characterized as having an endothermic peak at about 214° C. bydifferential thermal analysis.
 11. Valacyclovir hydrochloride form II ofclaim 7 characterized by the x-ray diffraction pattern substantially asshown in FIG.
 3. 12. Valacyclovir hydrochloride form IV. 13.Valacyclovir hydrochloride form IV of claim 12 characterized by thex-ray diffraction pattern substantially as shown in FIG.
 6. 14.Valacyclovir hydrochloride form IV of claim 12 characterized by x-raydiffraction reflections at about 3.6°, 10.7°, 15.1°, 26.9°, and28.1°±0.2° 2θ. 15 Valacyclovir hydrochloride in form IV of claim 14further characterized by x-ray diffraction reflections at about 7.2°,8.6°, 9.5°, 13.3°, 15.2°, 27.3°, and 28.1°±0.2° 2θ.
 16. Valacyclovirhydrochloride form IV of claim 14 further characterized as having awater content between about 8% and about 11% as measured bythermogravimetric analysis over the temperature range between about 25°C. and about 130° C.
 17. Valacyclovir hydrochloride form V. 18.Valacyclovir hydrochloride in form V of claim 17 characterized by thex-ray diffraction pattern substantially as shown in FIG.
 7. 19.Valacyclovir hydrochloride in form V of claim 17 characterized by x-raydiffraction reflections at about 6.7°, 15.7°, 16.2°, and 22.6°±0.2° 2θ.20. Valacyclovir hydrochloride in form V of claim 19 furthercharacterized by additional x-ray diffraction reflections at about 3.4°,9.5°, 13.5°, 21.9°, 27.2°, and 28.6°±0.2° 2θ.
 21. Valacyclovirhydrochloride in form V of claim 19 further characterized as having aweight loss of between abut 5% and about 7% as measured bythermogravimetric analysis over the temperature range between about 25°C. and about 130° C.
 22. Valacyclovir hydrochloride in form V of claim21 further characterized by a broad endothermic peak at about 95° C. anda sharp endothermic peak at about 180° C. in differential thermalanalysis.
 23. Valacyclovir hydrochloride in form VI.
 24. Valacyclovirhydrochloride form VI of claim 23 characterized by the x-ray diffractionpattern substantially as shown in FIG.
 9. 25. Valacyclovir hydrochloridein form VI of claim 23 characterized by x-ray diffraction reflections atabout 6.2°, 9.2°, 12.1°, 20.2° and 25.7°±0.2° 2θ.
 26. Valacyclovirhydrochloride in form VII.
 27. Valacyclovir hydrochloride form VII ofclaim 26 characterized by x-ray diffraction reflections at about 3.5°,10.3°, 13.6°, 26.2° and 28.1°±0.2° 2θ.
 28. The valacyclovirhydrochloride in form VII of claim 26 characterized by the x-raydiffraction pattern substantially as shown in FIG.
 10. 29. A method ofmaking valacyclovir hydrochloride form I comprising the step ofslurrying valacyclovir hydrochloride in a slurry solvent selected fromthe group consisting of ethyl acetate, acetone, methyl ethyl ketone,dioxane, methylene chloride, t-butyl methyl ether, and tetrahydrofurane.30. The method of claim 29 further comprising the steps of: isolatingvalacyclovir hydrochloride in form I from the slurry and dryingvalacyclovir form I at a temperature between about 50° C. and about 70°C.
 31. A method of making valacyclovir hydrochloride form II comprisingthe step of slurrying valacyclovir hydrochloride in a slurry solventselected from the group consisting of isopropyl alcohol, 1-butanol, andethanol.
 32. The method of claim 28 wherein the slurry solvent isisopropyl alcohol.
 33. A method of making valacyclovir hydrochlorideform II comprising the steps of: a, slurrying valacyclovir in a slurrysolvent selected from acetonitrille, methyl ethyl ketone, ethyl acetate,acetone, and toluene b, heating the slurry to reflux, c, refluxing theresulting mixture, and d, isolating valacyclovir hydrochloride in formII from the mixture.
 34. The method of claim 33 wherein the slurrysolvent is toluene and further comprising the step of adding methanol tothe refluxing mixture of valacyclovir hydrochloride and toluene.
 35. Themethod of claim 34 further comprising the step of drying the isolatedvalacyclovir hydrochloride form II at a temperature of about 60° C. 36.The method of claim 32 further comprising the step of drying theisolated valacyclovir hydrochloride form II at a pressure less thanabout 500 mm Hg and the temperature is about 50° C.
 37. A method ofmaking valacyclovir in form III comprising the step of incubatingvalacyclovir hydrochloride in an atmosphere saturated with vapors of atleast one incubating solvent selected from the group consisting ofisopropanol, ethanol, butanol, acetone, ethyl acetate, tetrahydrofurane,acetonitrile, and methanol.
 38. The method of claim 37 wherein thevalacyclovir hydrochloride is in solution in the incubating solvent. 39.The method of claim 37 wherein the valacyclovir hydrochloride is insolid form and the incubating solvent is acetonitrile.
 40. A method ofmaking valacyclovir hydrochloride form IV comprising the step ofincubating valacyclovir hydrochloride in an atmosphere saturated withvapors of an incubating solvent that is water.
 41. The method of claim40 wherein the incubating solvent is water and the atmosphere has arelative humidity of about 100%.
 42. A method of making valacyclovirhydrochloride in form V comprising the step of mixing a solution ofvalacyclovir hydrochloride in water with a lower aliphatic alcohol. 43.The method of claim 42 wherein the lower aliphatic alcohol isiso-propanol.
 44. A method of making valacyclovir in form VI comprisingthe step of mixing a solution of valacyclovir hydrochloride in a firstsolvent comprising water and an aliphatic monocarboxylic acid, with asecond solvent comprising a water-miscible ketone to form a suspension.45. The method of claim 44 wherein the first solvent comprises betweenabout 30% and about 60% by volume of water and wherein the amount of thesecond solvent is about 2 to about 5 times the volume of said firstsolvent.
 46. The method of claim 44 wherein the water-miscible ketone isacetone.
 47. The method of claim 44 further comprising the step offiltering the solution of valacyclovir hydrochloride in first solventbefore the mixing step.
 48. The method of claim 44 further comprisingthe steps of; agitating the suspension at a temperature less than about−10° C. and isolating valacycvlovir hydrochloride in form VI from thesuspension.
 49. A method of making valacyclovir in form VII comprisingthe step of mixing a solution of valacyclovir hydrochloride in a firstsolvent consisting essentially of water with a second solvent comprisinga water-miscible ketone to form a suspension.
 50. The method of claim 49wherein the water-miscible ketone is acetone.
 51. The method of claim 49further comprising the steps of: agitating the suspension at atemperature less than about −10° C.; and isolating valacyclovirhydrochloride in form VII from the suspension.
 52. A method of makingvalacyclovir hydrochloride in form I comprising the steps of dissolvingvalacyclovir hydrochloride in a solvent, and evaporating the solution ata reduced pressure.
 53. The method of claim 52 wherein the solvent is apolar organic solvent having 4 or fewer carbon atoms.
 54. The method ofclaim 53 wherein the polar organic solvent is an alcohol.
 55. The methodof claim 54 wherein the solvent is methanol.
 56. Valacyclovirhydrochloride monohydrate.
 57. A method of making valacyclovirmonohydrate comprising the step of contacting a solution of valacyclovirhydrochloride in water with iso-propanol to form a suspension.
 58. Themethod of claim 57 wherein the contacting is at a temperature of betweenabout 30° C. and about 50° C.
 59. The method of claim 58 wherein thecontacting is at a temperature of about 40° C.
 60. The method of claim57 further comprising the steps of isolating the solid from thesuspension and drying the isolated solid at a temperature of about 25°C. to constant weight.
 61. The method of claim 60 wherein the drying isat reduced pressure.
 62. A pharmaceutical composition comprising atleast one of valacyclovir hydrochloride in Forms I, II, IV, V, VI orVII.
 63. The pharmaceutical composition of claim 53 further comprisingat least one pharmaceutically acceptable excipient.
 64. Valacyclovirhydrochloride dihydrate.